The objective of the proposed study is to gain information concerning the molecular basis for drug abuse. It is proposed to study the possibility that morphine action, tolerance, and withdrawal symptoms may result from modifications of the cyclic nucleotide system in the brain. Specifically, the relationship of morphine to cyclic AMP, the cyclic AMP-receptor protein and phosphoprotein metabolism will be studied. The possibility that enkephalin from brain, a natural ligand for opiate receptors composed of two pentapeptides, is involved with the regulation of an enkephalin-sensitive adenylate cyclase will be investigated. Moreover, the effects of acute and of chronic administration of enkephalin, of morphine, as well as of morphine agonists and antagonists, will be studied on the cyclic AMP-receptor protein and on phosphoprotein metabolism in homogenates and slices of nervous tissue.